rs372347027

Positions:

chr1-215867179-T-C

Variant summary

Our verdict is Pathogenic. Variant got 5 ACMG points: 5P and 0B. PP3PP4PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The c.8682-9A>G variant in USH2A has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID:27318125, 25425308, 28944237, 23591405). The allele frequency of the c.8682-9A>G variant in the USH2A gene is 0.04% (5/10112) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). At least one patient with this variant displayed features of retinitis pigmentosa and hearing loss which is consistent with Usher syndrome (PP4; PMID:27318125, 25425308, 28944237, 23591405). Computational prediction tools and conservation analysis suggest that the c.8682-9A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PM2_Supporting, PP4, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA275277/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

USH2A
NM_206933.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9982

Clinical Significance

Pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: -0.0170

Variant links:

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 5 ACMG points.

PM2

PM3

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.8682-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.8682-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.8682-9A>G		splice_polypyrimidine_tract_variant, intron_variant					O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000680

AC:

AN:

249878

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135040

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461122

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726792

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000101

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2019	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 23591405, 18273898, 25425308, 27318125, 30358468, 28944237, 31980526, 33576794) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change falls in intron 43 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. This variant is present in population databases (rs372347027, gnomAD 0.05%). This variant has been observed in individual(s) with Usher syndrome type II (PMID: 18273898, 23591405, 25425308, 27318125, 28894305, 28944237). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197510). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -

Retinitis pigmentosa 39

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 17, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.8682-9A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 04, 2017	- -

Usher syndrome

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 24, 2018	The c.8682-9A>G variant in USH2A has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 27318125, 25425308, 28944237, 23591405). The allele frequency of the c.8682-9A>G variant in the USH2A gene is 0.04% (5/10112) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). At least one patient with this variant displayed features of retinitis pigmentosa and hearing loss which is consistent with Usher syndrome (PP4; PMID: 27318125, 25425308, 28944237, 23591405). Computational prediction tools and conservation analysis suggest that the c.8682-9A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PM2_Supporting, PP4, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 05, 2021	Variant summary: USH2A c.8682-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes canonical a 3 acceptor site. Two predict the variant creates a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-05 in 250002 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (6.8e-05 vs 0.011), allowing no conclusion about variant significance. c.8682-9A>G has been reported in the literature in multiple individuals affected with Usher Syndrome and Hereditary retinal dystrophies (e.g. Glockle_2013, Zein_2014, Hartel_2016, Neuhanus_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4) and likely pathogenic (n=5), including one expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 28, 2019

- -

Usher syndrome type 2A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 15, 2022

_x000D_ Criteria applied: PM3_VSTR, PS1_SUP, PP3 -

USH2A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2023

The USH2A c.8682-9A>G variant is predicted to interfere with splicing. This variant is predicted to create a cryptic splice acceptor site (Alamut Visual Plus v1.6.1). This variant was reported as pathogenic for autosomal recessive Usher syndrome (Glöckle. 2014. PubMed ID: 23591405; Zein. 2014. PubMed ID: 25425308; Table S4, Colombo. 2021. PubMed ID: 34781295). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216040521-T-C). This variant has been interpreted as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/197510/). This variant is interpreted as pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The c.8682-9A>G variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.95

Position offset: -1

DS_AL_spliceai

0.81

Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over